The HIV-1 reverse transcriptase (RT) heterodimer contains a peptide sequence which may function as a leucine zipper to stabilize subunit association. Molecular dynamics simulations of 100 ps duration in water at 300 K were performed on the RT peptide and on a portion of GCN4, which is known to form parallel alpha-helical dimers. Free energy calculations based on the solvent accessible surface area indicated a 2-5 kcal/mol difference favoring the antiparallel RT structure. In contrast, the expected parallel dimer was favored for GCN4: a relative stabilization of 10-13 kcal/mol was predicted. The results are consistent with stabilization of the RT dimer by a novel leucine zipper and suggest that the preferred orientation of the zipper peptides is antiparallel. They are also in accord with experimental observations on GCN4 and indicate that the hydrophobic effect is the dominant energetic factor driving the dimerization of this leucine zipper. Detailed analysis of side chain packing suggested empirical rules for predicting the orientation of such dimers. A manuscript is in preparation, and will be submitted to the journal "Proteins."